The Meyer-Overton rule states that the potency of an
anaesthetic is proportional to its lipid solubility. This suggests a lipophilic site
of action.

Lipid vs protein

Both involved

The most likely site of action are proteins, specifically ion channels, membrane
receptors and intracellular enzyme systems. The idea of a unitary theory of anaesthesia
must be considered obsolete. It is clear that drugs that act at multiple sites to
produce anaesthesia.

The GABA A receptor-chloride channel is a
ligand-gated inhibitory complex that contains modulatory sites for benzodiazepines,
barbiturates, etomidate, propofol, steroid anaesthetics and volatile anaesthetics.
Intravenous and inhalational anaesthetis also modulate the presynaptic release or uptake
of GABA

There are at least six different classes of voltage-sensitive calcium channels ,
at least three have been linked to the action of volatile and intravenous anaesthetics

T-type - T-type calcium channels are important in controlling the state
of the postsynaptic membranes in the brain. Volatile anaesthetics depress this
receptor in several cell types which, at least in part, accounts for their anaesthetic
action.

The difference between tissue and arterial volatile partial pressure (oil/water)

Blood/Gas

2.5

1.91

1.4

0.42

0.6

0.47

0.115

Oil/Water

220

120

170

18.7

55

3

20

Brain/Blood

1.9

1.4

1.9

1.3

1.7

1.1

Heart/Blood

1.8

?

1.6

1.3

1.8

1.1

Fat/Blood

51

36

45

27

48

2.3

Liver/Blood

2.1

2.1

1.8

1.3

1.8

0.8

Kidney/Blood

1.2

1

1.1

1

1.2

0.85

Muscle/Blood

3.4

1.7

2.9

2

3.1

1.2

M etabolism

Oxidation in the liver to T ri F luoro A cetic
acid and free fluoride ions

Hexa-fluoro- isopropyl

Nil

Nil

Reduction

Amount

20-50%

2%

0.2%

0.02%

2%

-

-

E xcretion

Breath and urine

Breath

Breath

C hemistry

Halothane

Enflurane

Isoflurane

Desflurane

Sevoflurane

Nitrous

Xenon

Halogenated Alkane

Halogenated Methyl ethyl ethers

Methyl- Isopropyl -ether

Gas

Nobel Gas

CF 3 CBrClH

CHFClCF 2 OCF 2 H

CF 3 CHClOCF 2 H

CH(CF 3 )2 0CH 2 F

CF 3 CFHOCF 2 H

N=N=O
N=N-O

Xe

D ose - Given via a calibrated vaporiser

A standard measure of potency is the Minimal Alveolar Concentration. This is the
alveolar concentration of an agent, at one atmosphere required to produce immobility in
50% of patients when exposed to a noxious stimulus (defined as skin incision in humans).

Note no mention of the times involved are mentioned and one presumes steady state.

MACawake - Allows a voluntary response to commands in 50% of patients, this is used to
imply the amnestic dose of the agent = 0.7 MAC for Halothane

Risk factors that increase the chances are:- late middle age (50), obesity and being
female.

Diagnosis: All other causes of jaundice must be considered and excluded before a
diagnosis of halothane related hepatitis can be made. The most important is to rule out
the various types of viral hepatitis, which may not be serologically positive in the early
postoperative period. Other causes include

Surgical complications, especially bile duct surgery,

Peri-operative hypotension;

Intra-abdominal sepsis and / or septicaemia;

Infections with CMV, EBV and toxoplasmosis;

Reactions to other drugs used before or during surgery;

Sickle-cell crisis

Mechanism of toxicity:

Type I halothane hepatitis : This is an asymptomatic rise in serum
transaminases 1-2 weeks after exposure, that resolves without treatment. Histologically
there is an acute hepatitis like picture. There have been many theories about the
causation of type I hepatitis.

Direct allergic reaction to the intact halothane molecule. This is not the case as a
protein complex is needed to trigger an immunological event. Unfortunately this simplistic
theory gave rise to the erroneous impression that halothane is safe to use again after 3
months, in spite of an earlier reaction.

Direct biochemical destruction of the liver by reductive metabolic intermediates
analogous to the liver damage caused by the free radical species formed during the
metabolism of carbon tetrachloride and chloroform.

Hepatic hypoxia can easily be precipitated by a minor degree of hypotension because of
the loss of the hepatic artery buffer reserve. The first step in the reductive pathway is
believed to be an insertion of a single electron into the halothane molecule to produce a
highly reactive metabolite which then undergoes debromination to another free radical
intermediate. The simplistic approach is that liver macromolecules interact with metabolic
intermediates or free radicals. Free radicals are moieties capable of independent
existence that contain one or more unpaired electrons. These free radicals capture
electrons from adjacent molecules and produce a chain reaction in which free radicals
beget other free radicals which, in effect go on a destructive rampage. This may cause an
autocatalytic peroxidative chain reaction in the liver, leading to breakdown and necrosis
of essential fatty acids, lipoproteins and cell membranes.

Type II halothane hepatitis :

This reaction is uncommon and unpredictable, there is clinical and laboratory evidence
of severe hepatic necrosis. There is no relationship between the amount of halothane used
and the likelihood of this reaction, but there does seem to be a correlation between the
amount of halothane used and the severity of the liver failure. Onset may be by the 7 th
day after administration or relatively delayed compared to direct hepatotoxic drugs e. g.
paracetamol, for up to 28 days. It is accompanied by the rapid development of jaundice,
raised liver enzymes, pyrexia, arthralgia, rash, and direct evidence of immune
sensitisation - eosinophilia, circulating immune complexes and a variety of autoantibodies
to normal tissue components. There is characteristically a very high mortality rate. There
are several case reports of halothane hepatitis in children and in anaesthetic personnel.

There is now strong evidence that this is due to an immune response directed against
hepatocytes. The most convincing evidence for this theory is that serum from patients with
type II halothane hepatitis contains antibodies that react with an acyl halide that is
covalently bounded to liver cell membranes (N-e-Lysine).
This acyl halide (CF 3 COCl) acts as an epitope or hapten that is presented to
the immunocompetant cells, setting up and antibody reaction. The acyl halide is a
mandatory precursor to the production of Trifluoroacetic acid (TFA), the major oxidative
metabolic breakdown product of halothane, enflurane, isoflurane and desflurane. Why only a
small percentage of patients amount an immune response appears to be related to a variety
of susceptibility factors

Abnormal expression of the protein bound epitope from the endoplasmic reticulum to the
cell surface.

Variability of lymphocyte damage by electrophilic metabolites

Variability of immunological factors

Variability of the natural tolerance to the protein bound epitope.

This has now given rise to the theory that if no reaction to halothane has occurred
within 28 days after exposure it is probably safe to give halothane again, but that if
there was any form of reaction to an halothane exposure it is never again safe to give
halothane. This leads to a practical difficulty, which is that Boyles machines that
have been used for halothane anaesthesia continue to emit halothane for some time after
the agent has been removed. This is due to absorption of halothane into the plastic
components of the system providing a reservoir. The anaesthetic machine should be flushed
free of halothane with 100% oxygen at a flow rate of 8L/Hr for 8 hours

Sevoflurane toxicity

Renal toxicity

Fluoride induced

Inorganic fluoride nephrotoxicity was first recognised in 1960 with the
introduction of methoxyflurane. A serum level > 50mmol/L
over a prolonged period of time i. e. the area under the graph, was associated with
polyuria, proteinuria, glycosuria, impaired renal concentrating ability with a lack of
response to vasopressin and an increased serum sodium, urea, creatinine and osmolarity.
Sevoflurane metabolism readily releases inorganic fluoride with concentrations exceeding
50mmol/L after 2 MAC hours. However after extensive use for
prolonged periods of time in Japan there have been no reports of renal dysfunction - Why?

The peak fluoride level is short lived in sevoflurane anaesthesia because
the low blood/gas solubility coefficient allows rapid removal of the agent via the breath.
This decreases the area under the curve considerably.

The fluoride liberated during methoxyflurane anaesthesia appeared to be
produced in the kidney and was able to cause the damage directly. Sevoflurane is
metabolised four times less readily in the kidney with lower fluoride levels within the
kidney.

Compound A induced

Sevoflurane undergoes spontaneous degradation, to compound A-E, when
exposed to high temperatures (>50 o C) that occur in sodalyme and baralyme.
Compound A has been found to be nephrotoxic in rats but never in humans - Why?

The amount of compound A is dependant on the temperature of the absorber,
Sodasor is the most commercially used product and produces the lowest temperature 40 o C
because of the lack of KOH.

The fresh gas flow used is very seldom minimal today and so helps wash out
compound A

The nephrotoxicity in rats is because of b
lyase metabolism, in the rat kidney, to a reactive thiadacyl intermediate that does the
damage. Human kidney renal b lyase activity is much lower
than the rats.

Hepatitis

Oxidative metabolism of sevoflurane produces no reactive intermediaries
and so is incredibly unlikely to ever be associated with an immune linked hepatotoxicity.
This makes sevoflurane the agent of choice in a patient who has documented
sensitivity to the reactive intermediary produced during trifluoroacetic acid production.

Guedals stages of anaesthesia

STAGE

RESPIRATION

EYES PUPIL

REFLEX

One- Analgesia

regular small volume

Central small

Two - Excitement

Irregular

Divergent large

eyelash absent

Three- Anaesthesia
Plane I

Regular Large volume

Central small

eyelid absent and conjunctival depressed

Plane II

Regular Large volume

Central medium

corneal depressed

Plane III

Regular becoming diaphragmatic small
volume

Central medium

Laryngeal depressed

Plane IV

Irregular diaphragmatic small volume

Central large

Carinal depressed

Four - Overdose

Apnoea

Central full dilatation

Cardiac depressed

Desflurane vaporiser

Desflurane with its boiling point of 22.8 o C if administered in a
conventional plenum vaporiser could produce disastrous changes in output with small
increases in temperature. If the vaporiser temperature rose above the boiling point a
continuous flow of gaseous agent would be produced until all the liquid evaporated, or
until the latent heat of vaporisation resulted in the temperature being lowered below the
boiling point. The boiling point is so close to that of room temperature, that so called
"temperature compensators" would be inadequate. The alternative approach, used
with nitrous oxide, to contain the liquid in a cylinder and draw off the gas is also
impractical because at room temperature the saturated vapour pressure is too low. These
are overcome using a vaporiser with a sump heater so that vapour pressure is raised to
around two atmospheres absolute pressure (37 o C) internally and then dispensed
using a system of differential pressure transducers and variable resistance. The vapour
can be mixed with fresh gas using a metering valve. The entire vapour pathway is heated to
prevent the high partial pressure of the agent (potentially above the saturated vapour
pressure at room temperature) from "raining out".

Despite the high cost of xenon, xenon anaesthesia will
become possible at a reasonable cost. The hourly uptake of xenon decreases rapidly
and with full recycling of the gas during closed circuit anaesthesia, xenon anaesthesia
will be economically viable.

Physical properties

Colourless, odourless, tasteless.

Monatomic gas, atomic number = 54, molecular weight = 131,3

Gas under normal temperature and pressure

9 stable isotopes.

Freezing point -111,9 o C, Boiling point -108,1 o C.

4 times more dense than air.

Nonflammable and will not support combustion.

Diffuses freely through rubber and silicone components.

Manufactured by separation from liquid air, often as a by
product of steel making.

Anaesthetic agent

First used in 1951 by Cullen on an 81yr old man having an
orchidectomy..

The analgesic action of nitrous oxide involves the
descending inhibitory system from the brainstem. Xenon probably has a direct
suppressive action on spinal dorsal horn neurons

No occupational/ environmental disadvantages.

Specific effects on the body

Respiratory

Central depression causes a decrease in respiratory rate
with a compensatory increase in tidal volume and can progress to apnoea

Higher density and viscosity (compared with oxygen, air
and N 2 O) theoretically makes xenon more
likely to increase airway resistance. Clinically the airway resistance is slightly less
than that seen with N 2 O and it can be used safely
in lung disease

Diffusion hypoxia is very mild as the blood/gas partition
of Nitrogen (0.014) is only almost 10 times less than that of Xenon (0.115) as opposed to
the almost 40 times less than Nitrous Oxide (0.47)

Inhaled xenon when used as a tracer for the
measurement of cerebral blood flow increases cerebral blood flow, increases intracranial
pressure and decreases cerebral perfusion pressure in acute head injury patients.
This is not associated with cerebral oligaemia or ischaemia. This increase in
cerebral blood flow is reversed by mild hyperventilation and so might have been a result
of poorly controlled physiological variables. Hypercarbic induced vasodilatation
induced by the sedative effects of the inhaled xenon, and the stress effect of breathing a
dense gas mixture.

At present its use in neurosurgery is controversial

Renal

No data available.

Endocrine/neurohumoral

Attenuates surgical stress due to
analgesia. Does not have any short or long term cortisol suppression effects.